Predictions for Epicardial Ventricular Action Potentials of Healthy and Diabetic Rats

Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca²⁺-independent transient outward K⁺ current (I_t) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na⁺ current (I_Na) in the endocardial myocytes results in a faster upstroke (dV/dt_max). This, in addition to the smaller magnitude of I_t, is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K⁺ current (I_ss), and a larger influx of Ca²⁺ ions via the L-type Ca²⁺ current (I_CaL). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca²⁺ transient [Ca²⁺]_i, and the resultant increase in the Na⁺-Ca²⁺ exchanger (I_NaCa) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle.